Increased intake of calories coupled with decreased energy expenditure has fueled an epidemic of obesity, insulin resistance, and type 2 diabetes mellitus in the United States. In 2008, based on the body mass index (BMI), approximately 72.5 million adults in the United States were classified as being obese (BMI >30). Obesity is an independent risk factor for development of various chronic diseases, including type 2 diabetes, coronary heart disease, hypertension, stroke, certain types of cancer, and premature death. In addition to its impact on disease and life expectancy, the medical care costs of obesity in the United States are staggering, exceeding $147 billion in 2008. Thus, to blunt the eventual impact of this epidemic, it is extremely important to understand the molecular and cellular determinants that control energy expenditure and obesity. Fundamentally, there are two major ways of combating obesity: to decrease energy intake or to increase energy expenditure. In this regard, careful studies in rodents have demonstrated that activation of nonshivering thermogenesis in brown adipose tissue increases energy expenditure and confers protection against obesity. Moreover, the recent discovery of brown adipose tissue in humans suggests that activation of brown fat might be useful in the treatment of human obesity. While significant progress has been made on the molecular pathways controlling the differentiation of brown adipocytes, little is known about extrinsic signaling pathways that regulate brown adipose tissue physiology and energy expenditure. Remarkably, we have discovered that cells of the innate immune system take residence in brown adipose tissue, raising the possibility that the innate immune system might coordinate nonshivering thermogenesis in animals, and perhaps, humans. We thus propose three specific aims to explore this hypothesis, which are: 1) Investigate the regulatory role of macrophages in nonshivering thermogenesis, 2) Investigate the mechanisms by which macrophages in brown adipose tissue regulate uncoupled respiration and energy expenditure, and 3) Investigate the trafficking and functions of other immune cells in cold- and diet-induced thermogenesis. PUBLIC HEALTH RELEVANCE: Obesity, which is now a global health problem, results when energy intake exceeds energy expenditure. In both mice and humans, activation of brown adipose tissue increases energy expenditure, resulting in protection from obesity. Thus, studies in this grant application will elucidate novel cellular circuits that control cold- and diet-induced thermogenesis in brown adipose tissue.